Nociceptin (the same substance as orphanin FQ) is a peptide comprising 17 amino acids and having a similar structure to that of opioid peptide. Nociceptin has an augmenting activity on reaction against nociceptive stimulation, an appetite stimulating activity, an activity for reducing a space learning ability, an antagonism against an analgesic action of classic opiate agonists, a dopamine release inhibitory action, a water diuresis action, a vasodilative action and a systemic blood pressure-lowering action, and it is considered to take part in controlling pain, appetite and memory learning through a nociceptin receptor ORL1 [refer to Nature, vol. 377, p. 532 (1995); Society for Neuroscience, vol. 22, p. 455 (1996); NeuroReport, vol. 8, p. 423 (1997); Eur. J. Neuroscience, vol. 9, p. 194 (1997); Neuroscience, vol. 75, pp. 1 and 333 (1996); and Life Science, vol. 60, pp. PL15 and PL141 (1997)]. Further, it is known that morphine tolerance is reduced or memory and learning ability are improved in knockout mice in which expression of nociceptin receptor ORL1 is inhibited [Neuroscience Letters, vol. 237, p. 136 (1997)]; Nature, vol. 394, p. 577 (1998)].
Therefore, substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1 are useful as an analgesic against diseases accompanied with pain such as cancerous pain, postoperative pain, migraine, gout, chronic rheumatism, chronic pain and neuralgia; a reliever against tolerance to narcotic analgesic represented by morphine, a reliever against dependence on narcotic analgesic represented by morphine, an analgesic enhancer, an antiobestic, a drug for ameliorating brain function, a prophylactic for Alzheimer's disease, a drug for treating Alzheimer's disease, a prophylactic for dementia, an anti-dementia drug, a remedy for schizophrenia, a drug for treating regressive neurodegenerative diseases represented by Parkinsonism and chorea, an antidepressant, a remedy for diabetes insipidus, a remedy for polyuria or a remedy for hypotension.
Substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1 are described, for example, in International Publications WO00/27815A, WO99/59997A, WO99/48492A and WO99/36421A or EPO Publication EP963987A2. None of those is a compound having a skeletal structure of benzimidazole, and it was entirely unknown that those benzimidazole derivatives of the present invention can be such substances which specifically inhibit binding of nociceptin to nociceptin receptor ORL1.
On the other hand, compounds having structures analogous to those of the benzimidazole derivatives of the invention are described, for example, in JP-A-Sho 63(1988)-91385 or JP-A-Hei 2(1990)-306916. However, those compounds which have a specific aliphatic group on 2-position of benzimidazole skeletal structure, bound through or not through a hetero atom, have a specific substituent group on 5-position and furthermore have an aliphatic, nitrogen-containing heterocyclic group on 6-position, which are characteristic of the compounds of the invention, are not specifically disclosed in above-cited references, and they are compounds not hitherto disclosed in literature.
For example, in those benzimidazole derivatives disclosed in JP-A-Sho 63(1988)-91385, the part of substituent G corresponding to the structure of the present invention is methylene group having an aromatic group as the substituent, and they are different from the compounds of this invention. JP-A-Hei 2(1990)-306916 shows a structure analogous to that of the compounds of the present invention, but contains no disclosure on such specific structure of benzimidazole skeleton having a specific aliphatic group at its 2-position, a specific substituent group at 5-position and further an aliphatic, nitrogen-containing heterocyclic group at 6-position, the characteristic of the compounds of the present invention. Furthermore, the benzimidazole derivatives described in JP-A-Sho 63-91385 have use as anti-ulcer drug, while the benzimidazole derivatives described in JP-A-Hei 2-306916 are used for a platelet adhesion-inhibiting agent. Neither of them have antagonism to nociceptin receptor of the present invention.